Ilyas Khan,Sunan Li,Lihong Tao,Chong Wang,Bowei Ye,Huiyu Li,Xiaoyang Liu,Iqbal Ahmad,Wenqiang Su,Gongxun Zhong,Zhiyuan Wen,Jinliang Wang,Rong-Hong Hua,Ao Ma,Jie Liang,Xiao-Peng Wan,Zhi-Gao Bu,Yong-Hui Zheng

Nat Commun.2024 Jan 2;15(1):162.doi: 10.1038/s41467-023-44504-4.

Abstract

SARS-CoV-2 and filovirus enter cells via the cell surface angiotensin-converting enzyme 2 (ACE2) or the late-endosome Niemann-Pick C1 (NPC1) as a receptor. Here, we screened 974 natural compounds and identified Tubeimosides I, II, and III as pan-coronavirus and filovirus entry inhibitors that target NPC1. Using in-silico, biochemical, and genomic approaches, we provide evidence that NPC1 also binds SARS-CoV-2 spike (S) protein on the receptor-binding domain (RBD), which is blocked by Tubeimosides. Importantly, NPC1 strongly promotes productive SARS-CoV-2 entry, which we propose is due to its influence on fusion in late endosomes. The Tubeimosides' antiviral activity and NPC1 function are further confirmed by infection with SARS-CoV-2 variants of concern (VOC), SARS-CoV, and MERS-CoV. Thus, NPC1 is a critical entry co-factor for highly pathogenic human coronaviruses (HCoVs) in the late endosomes, and Tubeimosides hold promise as a new countermeasure for these HCoVs and filoviruses.